The avermectins (previously referred to as C-076 comopunds) are a series of compounds produced by fermentation of avermectin producing strains of Streptomyces avermitilis and derivatives thereof. The morphological characteristics of the culture are completely described in U.S. Pat. No. 4,310,519. The production, isolation, and structure determination of the avermectins are fully described in Albers-Schonberg et al J. Am. Chem. Soc. 1981, 103, 4216-4221 and references cited therein. The conversion of natural avermectin B.sub.1 to 22,23-dihydro-avermectin B.sub.1, the potent broad spectrum anthelminthic agent known as ivermectin, has also been described in the literature (Chabala et al J. Med. Chem. 1980, 23, 1134-1136). The naturally occurring avermectins and the instant derivatives thereof have a very high degree of anthelminthic and anti-parasitic activity.
The naturally occurring avermectins are a series of macrocyclic lactones which are substituted at position 13 with a disaccharide consisting of two oleandrose residues. The preparation and properties disaccharide moiety has been removed leaving a free hydroxyl group at position 13 have been described by Mrozik et al J. Org. Chem. 1982, 47, 489-492 and by Chabala et al J. Med. Chem. 1980, 23, 1134-1136. The natural compounds have the following general structure: ##STR1## wherein the broken line indicates a single or double bond and; R.sub.1 is hydroxy and is present only when said broken line indicates a single bond;
R.sub.2 is iso-propyl or sec-butyl; and PA1 R.sub.3 is methoxy or hydroxy. PA1 X=--(CH.sub.2).sub.n --, --CH.sub.2 CH.sub.2 OCH.sub.2 --; PA1 n=2-5; PA1 R.sub.5 =OH, oxime; PA1 R.sub.23 =H, OH, oxo (OH or oxo only if the broken line is a single bond); PA1 R.sub.25 =lower alkyl, lower alkenyl; PA1 X=--(CH.sub.2).sub.n --, --CH.sub.2 CH.sub.2 OCH.sub.2 --; PA1 n=2-5; PA1 R.sub.5 =OH; PA1 R.sub.4 "=OH, NH.sub.2, NH(lower alkyl), NH(lower alkanoyl); PA1 R.sub.23 =H, OH, oxo (OH or oxo only if the broken line is a single bond); PA1 R.sub.25 =lower alkyl; PA1 X=--(CH.sub.2).sub.n --; PA1 n=2-5; PA1 R.sub.5 =OH; PA1 R.sub.4 "=OH, NH(lower alkanoyl); PA1 R.sub.23 =H, OH, (OH only if the broken line is a single bond); PA1 R.sub.25 =isopropyl or sec-butyl; PA1 X=--(CH.sub.2).sub.n --; PA1 n=2 or 3; PA1 R.sub.5 =OH; PA1 R.sub.4 "=OH; PA1 R.sub.23 =H; PA1 R.sub.25 =isopropyl or sec-butyl;
There are eight major natural avermectin compounds, designated A.sub.1a, A.sub.1b, A.sub.2a, A.sub.2b, B.sub.1a, B.sub.1b, B.sub.2a and B.sub.2b. These designations are based on the structure of the individual compounds as shown in the following table (referring to the foregoing structura formula).
______________________________________ Compound broken line R.sub.1 R.sub.2 R.sub.3 ______________________________________ A.sub.1a double bond -- sec-butyl --OCH.sub.3 A.sub.1b double bond -- iso-propyl --OCH.sub.3 A.sub.2a single bond --OH sec-butyl --OCH.sub.3 A.sub.2b single bond --OH iso-propyl --OCH.sub.3 B.sub.1a double bond -- sec-butyl --OH B.sub.1b double bond -- iso-propyl --OH B.sub.2a single bond --OH sec-butyl --OH B.sub.2b single bond --OH iso-propyl --OH ______________________________________
The avermectins are generally isolated as mixtures of the a and b components (typically .gtoreq.80% a and .ltoreq.20% b). Such compounds differ only in the nature of the R.sub.2 substituent and this minor structural difference has been found to have very little effect on the chemical reactivity or biological activity of the compounds. Thus although the a and b components can be separated from each other by chromatography this is not necessary and hence is not normally done. The presence of a mixture of a and b components is indicated by dropping the a or b from the designation of the compound. A mixture of avermectin B.sub.1a and avermectin B.sub.1b is thus referred to as avermectin B.sub.1.
A related family of natural products is known as the milbemycins. The milbemycins have the same basic structure as the avermectins but have no substitution at position 13 and have a methyl or ethyl group at position 25 (R.sub.2 =methyl or ethyl rather than isopropyl or sec-butyl as in the avermectins). The milbemycins and the fermentation conditions used to prepare them are described in U.S. Pat. No. 3,950,360. Closely related 13-deoxyavermectin aglycones are prepared by chemical modification of the natural avermectins and have been described in U.S. Pat. Nos. 4,171,134 and 4,173,571.
Recently a number of related compounds have been described in European Patent Application EPO 170,006 and U.K. aplication 2,166,436 (see also Carter et al, J. Antibiotics 1988, 41, 519-529). These compounds are essentially 13-deoxy-avermectin aglycones in which the 25-position side chain contains a double bond and, in some cases, includes additional carbon atoms. In addition, GB 2167751 describes certain 13-substituted milbemycin compounds which are related to the starting materials for the instant compounds.